Breast cancer remains one of the deadliest diseases in women. According to American Cancer Society about 230,480 women in the US were diagnosed with invasive breast cancer in 2011 and about 40,000 died in that year. Also, a 2009 study by the Walter Reed Army Med. Ctr. suggested that women in the army are 20-40% more likely to develop breast cancer. Therefore, a greater understanding of breast cancer and better therapeutic strategies are urgently needed. This proposal focuses on the fork-head box transcription factor FoxM1 that is over-expressed in the aggressive forms of breast cancers, including the Basal type(s) of breast cancer. Moreover, over-expression of FoxM1 coincides with metastasis and is a biomarker for poor prognosis. In this proposal, we plan to evaluate the functions of FoxM1 in normal mammary gland as well as in the mechanisms that lead to the development of aggressive breast cancer. In addition, we will determine whether targeting FoxM1 using a specific peptide-inhibitor inhibits metastatic progression of breast cancer. The proposal is based on a newly discovered function of FoxM1 in repression of GATA-3 in mammary gland. FoxM1 is expressed at a high level in the luminal progenitor cells. GATA-3 induces differentiation of those progenitors. We will test the hypothesis that FoxM1 controls excessive differentiation during pregnancy, and thus plays an important role in maintaining plasticity of the mammary gland. GATA-3 also is a suppressor of metastasis in breast cancer. Therefore, we will investigate the hypothesis that the repression function of is critical to the mechanism by which FoxM1 contributes to the development of highly aggressive breast cancer. We have characterized a highly specific peptide inhibitor of FoxM1 derived from the tumor suppressor p19ARF that in a cell- penetrating form (ARF-peptide) inhibits metastatic colonization of liver cancer, p53-null sarcoma and p53-null lymphoma. We will investigate whether that peptide-inhibitor efficiently blocks metastatic progression and/or sensitizes breast cancers to available therapies, such as Taxol. The specific aims are: Aim1: Investigate the roles of FoxM1 in mammary gland. Aim2: Investigate the roles of FoxM1 in the metastatic progression of breast cancer. Aim3: Investigate whether the ARF-derived peptide inhibitor of FoxM1 inhibits mammary tumor progression. This merit review proposal is in response to BLR&D RFA on Women's Health. As more women are entering the US Army, health care at the VA with regards to invasive breast cancer is becoming increasingly significant. Our studies will investigate several novel hypotheses, which will be insightful in understanding and in therapy of metastatic breast cancers.